Diaminocyclobutene-3,4-diones

ABSTRACT

The compound of the formula: ##STR1## wherein R 1  and R 2  are, independent from each other, hydrogen, alkyl or cyclic or bicyclic alkyl; R 3  is an acyl substituent selected from the group consisting of formyl, alkanoyl, alkenoyl, alkylsulfonyl, aroyl, arylalkenoyl, arylsulfonyl, arylalkanoyl or arylalkylsulfonyl; A is selected from the group consisting of: ##STR2## wherein R 4  is hydrogen, alkyl, perfluoroalkyl, alkoxy, perfluoroalkoxy, amino, alkylamino, dialkylamino, alkylsulfonamido, alkylcarboxamido, nitro, cyano or carboxyl; or a pharmaceutically acceptable salt thereof, are smooth muscle relaxants.

This is a division of application Ser. No. 08/340,697 filed Nov. 16,1994 now U.S. Pat. No. 5,464,867, issued Nov. 7, 1995.

BACKGROUND OF INVENTION

The present invention relates to novel 1,2-diamino derivatives ofcyclobutene 3-4-diones having pharmacological activity, to a process fortheir preparation, to pharmaceutical compositions containing them, andto their use in the treatment of disorders associated with smooth musclecontraction; via potassium channel modulation. Such disorders include,but are not limited to: urinary incontinence, hypertension, asthma,premature labor, irritable bowel syndrome, congestive heart failure,angina, and cerebral vascular disease.

Stemp et al. disclose a class of amino substituted cyclobutenedionederivatives of chromans described as having blood pressure loweringactivity and bronchodilatory activity in EP-426379-A2. Several series of1-amino-2 -phenylalkylamino-cyclobutene-3,4-diones are reported as H-2receptor antagonists by Algieri et al. in U.S. Pat. No. 4,390,701.Several related 1-amino-2-phenoxyalkylamino derivatives are disclosed byNohara et al. in U.S. Pat. No. 4,673,747.

The syntheses of variously substituted1,2-diamino-cyclobutene-3,4-diones are described in the followingpublications: Tietze et al., Chem Ber. 1991, 124, 1215; Tietze et al.,Bioconjugate Chem. 1991, 2, 148; Ehrhardt et al., Chem. Ber. 1977, 110,2506, and Neuse et al., Liebigs Ann. Chem. 1973, 619. For example, Neuseet al. discloses 1-phenylamino-2-dimethylamino-cyclobut-1-ene-3,4-dione.The compounds of the present invention differ from the Neuse et al.compound in that they are N-acylated and they are useful as smoothmuscle relaxants.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a group ofcompounds represented by the formula (I): ##STR3## wherein: R₁ and R₂are, independent from each other, hydrogen, C₁₋₁₀ straight chain alkyl,C₁₋₁₀ branched alkyl, or C₃₋₁₀ cyclic or bicyclic alkyl;

R₃ is an acyl substituent selected from the group consisting of formyl,alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms,alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms,arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbonatoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkylsulfonyl of 7 to12 carbon atoms;

A is selected from the group consisting of: ##STR4## wherein: R₄ ishydrogen, C₁₋₆ alkyl, C₁₋₆ perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆perfluoroalkoxy, amino, C₁₋₆ alkylamino, C₂₋₁₂ dialkylamino, C₁₋₆alkylsulfonamido, alkylcarboxamido containing 2 to 7 carbon atoms,nitro, cyano, carboxyl;

or, A is a substituted phenyl group of the following formula: ##STR5##wherein: R₅ and R₆, independent from each other, are selected from thefollowing: cyano, nitro, amino, C₁₋₆ alkyl, C₁₋₆ perfluoroalkyl, C₁₋₆alkoxy, C₁₋₆ perfluoroalkoxy, C₁₋₆ alkylamino, C₂₋₁₂ dialkylamino,sulfamyl, C₁₋₆ alkylsulfonamido, C₆₋₁₂ arylsulfonamido, alkylcarboxamidocontaining 2 to 7 carbon atoms, arylcarboxamido containing 7 to 13carbon atoms, C₂₋₆ alkanoyl, C₁₋₆ alkylsulfonyl, C₁₋₆perfluoroalkylsulfonyl, C₆₋₁₂ arylsulfonyl, chloro, bromo, fluoro, iodo,1-imidazolyl, carboxyl or hydrogen;

or a pharmaceutically acceptable salt thereof.

A preferred aspect of this invention includes compounds of formula (I)wherein:

R₁ and R₂ are as stated above;

A is selected from the following: ##STR6## wherein: R₄ is as statedabove:

or, A is a substituted phenyl group of the following formula: ##STR7##wherein: R₅ and R₆, independent from each other, are selected from thefollowing: cyano, nitro, amino, chloro, bromo, fluoro, iodo,1-imidazolyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbonatoms, perfluoroalkyl of 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbonatoms, carboxyl or hydrogen;

or a pharmaceutically acceptable salt thereof.

The most preferred aspect of this invention includes compounds offormula (I) wherein:

R₁ and R₂ are as stated above;

A is selected from the following: ##STR8## wherein: R₄ is as statedabove;

or, A is a substituted phenyl group of the following formula: ##STR9##wherein: R₅ and R₆, independent from each other, are selected from thefollowing: cyano, nitro, amino, chloro, bromo, fluoro, iodo,1-imidazolyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbonatoms, perfluoroalkyl of 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbonatoms, carboxyl or hydrogen;

or a pharmaceutically acceptable salt thereof.

It is understood that the definition of the compounds of formula (I),when R₁, R₂, R₃, R₄. or R₅ contain asymmetric carbons, encompass allpossible stereoisomers and mixtures thereof which possess the activitydiscussed below. In particular, it encompasses racemic modifications andany optical isomers which possess the indicated activity. Opticalisomers may be obtained in pure form by standard separation techniquesor enantiomer specific synthesis. The compounds of this invention,throughout this specification, are equivalently name as 3,4-diones or1,2-diones. The pharmaceutically acceptable salts of the basic compoundsof this invention are those derived from such organic and inorganicacids as: lactic, citric, acetic, tartaric, succinic, maleic, malonic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, and similarly known acceptable acids. Where R₃, R₄, orR₅ is a carboxyl group, salts of the compounds of this invention may beformed with bases such as alkali metals (Na, K, Li) or the alkalineearth metals (Ca or Mg).

The present invention also provides a process for the preparation of acompound of formula (I). More particularly, the compounds of formula (I)may be prepared by reacting a compound of formula (IIa): ##STR10##wherein X is a leaving group, for example, methoxy, ethoxy, isopropoxy,halogen or a similar leaving group and A₁ is A and R_(a3) is R₃, asdefined hereinbefore or a group of atoms convertible thereto, with acompound of formula (IV): ##STR11## wherein R_(a1) and R_(a2) are R₁ andR₂, respectively, as defined hereinbefore or a group of atomsconvertible thereto and, where appropriate, converting A₁ into A orconverting R_(a1) into R₁ or converting R_(a2) into R₂, followed byreacylation if necessary and, where desired, converting a compoundhaving formula (I) into a pharmaceutically acceptable salt thereof orconverting a salt of a compound having formula (I) into a compoundhaving formula (I).

The compounds having formula (IIa) may be prepared by reaction of acompound of formula (II): ##STR12## where X is as defined above with acompound of formula (III):

    A.sub.1 --NH.sub.2                                         (III)

wherein A₁ is as defined above, followed by acylation to provide R_(a3).Of course, acylation may also be conducted after reaction of the A₁substituted compound with HNR_(a1) R_(a2).

The reactions mentioned above may be carried out in a solvent such asacetonitrile, methanol or ethanol at elevated or ambient temperatures.

As mentioned previously, the compounds of formula (I) and theirpharmaceutically acceptable salts have been found to relax smoothmuscle. They are therefore useful in the treatment of disordersassociated with smooth muscle contraction, disorders involving excessivesmooth muscle contraction of the urinary tract (such as incontinence),or of the gastro-intestinal tract (such as irritable bowel syndrome),asthma, and hair loss. Furthermore, the compounds of formula (I) areactive as potassium channel activators which render them useful fortreatment of peripheral vascular disease, hypertension, congestive heartfailure, stroke, anxiety, cerebral anoxia and other neurodegenerativedisorders.

The present invention accordingly provides a pharmaceutical compositionwhich comprises a compound of this invention in combination orassociation with a pharmaceutically acceptable carrier. In particular,the present invention provides a pharmaceutical composition whichcomprises an effective amount of a compound of this invention and apharmaceutically acceptable carrier.

The compositions are preferably adapted for oral administration.However, they may be adapted for other modes of administration, forexample, parenteral administration for patients suffering from heartfailure.

In order to obtain consistency of administration, it is preferred that acomposition of the invention is in the form of a unit dose. Suitableunit dose forms include tablets, capsules and powders in sachets orvials. Such unit dose forms may contain from 0.1 to 100 mg of a compoundof the invention and preferably from 2 to 50 mg. Still further preferredunit dosage forms contain 5 to 25 mg of a compound of the presentinvention. The compounds of the present invention can be administeredorally at a dose range of about 0.01 to 100 mg/kg or preferably at adose range of 0.1 to 10 mg/kg. Such compositions may be administeredfrom 1 to 6 times a day, more usually from 1 to 4 times a day.

The compositions of the invention may be formulated with conventionalexcipients, such as a filler, a disintegrating agent, a binder, alubricant, a flavoring agent and the like. They are formulated inconventional manner, for example, in a manner similar to that used forknown antihypertensive agents, diuretics and β-blocking agents.

The present invention further provides a compound of the invention foruse as an active therapeutic substance. Compounds of formula (I) are ofparticular use in the induction of smooth muscle relaxation.

The present invention further provides a method of treating smoothmuscle disorders in mammals including man, which comprises administeringto the afflicted mammal an effective amount of a compound or apharmaceutical composition of the invention.

The following examples are presented to illustrate rather than limit themethods for production of representative compounds of the invention.

EXAMPLE 1N-(4-Cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-propionamide

4-Aminobenzonitrile (17.58 g, 149 mmol) was added to a solution of3,4-diethoxy-3-cyclobutene-1,2-dione (25.31 g, 149 mmol) in absoluteethanol (450 mL). The mixture was heated at reflux overnight and theresulting suspension filtered hot to remove a small amount of a dirtyyellow solid (discarded). The filtrate was gradually concentrated toafford several crops of4-(3,4-dioxo-2-ethoxy-cyclobut-1-enylamino)benzonitrile, as a brightyellow solid, which were collected by filtration and combined. Yield:29.11 g (81%): ¹ H NMR (DMSO-d₆): δ11.07 (s, 1H), 7.81 (d, 2H), 7.56 (d,2H), 4.79 (q, 2H), 1.46 (t, 3H).

To the product of the preceding paragraph (13.00 g, 53.7 mmol) inethanol (360 mL) was added 2-amino-3,3-dimethylbutane (7.2 mL, 54 mmol).The mixture was heated at reflux overnight. Gradual concentration of thereaction solution afforded two crops of4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-benzonitrile,as a yellow precipitate, which were collected by filtration andcombined. Yield: 11.34 g (71%): ¹ H NMR (DMSO-d₆): δ9.89 (s, 1H), 7.78(d, 2H), 7.72 (d, 1H), 7.60 (d, 2H), 3.96 (m, 1H), 1.18 (d, 3H), 0.91(s, 9H).

To a solution of the product of preceding paragraph (1.20 g, 4.04 mmol)in N,N-dimethylformamide (36 mL) was added, in one portion, sodiumhydride (as a 60% dispersion in mineral oil; 0.179 g, 4.48 mmol). Thefrothy suspension was stirred at room temperature for 15 minutes andthen at 0° C. for an additional hour. Propionic anhydride (0.57 mL, 4.45mmol) was added and the reaction mixture was stirred at 0° C. for 15minutes and then allowed to warm to room temperature. After stirringovernight, the reaction mixture was concentrated. The resulting residuewas taken up in methylene chloride and washed with aqueous sodiumbicarbonate, brine and water. The organic layer was dried (Na₂ SO₄) andconcentrated to afford a yellow foam which was purified bychromatography (CH₃ OH/CH₂ Cl₂) and trituration (Et₂ O) to afford 0.68 g(48%) ofN-(4-cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethylpropylamino)-cyclobut-1-enyl]-propionamideas a light yellow solid: mp 211°-214° C.; ¹ H NMR (CDCl₃): δ7.81 (d,2H), 7.50-7.42 (m, 3H), 4.28 (m, 1H), 2.18 (m, 2H), 1.26 (d, 3H), 1.10(t, 3H), 1.00 (s, 9H). IR (KBr): 3330, 2230, 1800, 1740, 1690, 1620 cm⁻¹; MS (m/z) 353 (M⁺).

Elemental analysis for C₂₀ H₂₃ N₃ O₃ Calc'd: C, 67.97; H, 6.56; N,11.89. Found: C, 67.77; H, 6.35; N, 11.87.

EXAMPLE 2N-(4-Cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-benzamide

To a solution of the intermediate produced in Example 1, secondparagraph (1.20 g, 4.04 mmol) in N,N-dimethylformamide (36 mL) wasadded, in one portion, sodium hydride (as a 60% dispersion in mineraloil; 0.178 g, 4.45 mmol). The frothy suspension was stirred at roomtemperature for 15 minutes and then at 0° C. for an additional hour.Benzoic anhydride (1.01 mL, 4.46 mmol) was added and the reactionmixture was stirred at 0° C. for 15 minutes and then allowed to warm toroom temperature. After stirring overnight, the reaction mixture wasconcentrated. The resulting residue was taken up in methylene chlorideand washed with aqueous sodium bicarbonate, brine and water. The organiclayer was dried (Na₂ SO₄) and concentrated to afford a yellow foam whichwas purified by chromatography (CH₃ OH/CH₂ Cl₂) and trituration (diethylether) to afford 0.71 g (44%) of product as a pale yellow solid: mp229°-231° C.; ¹ H NMR (CDCl₃): δ7.61-7.22 (m, 9H), 7.77 (d, 1H), 4.37(m, 1H), 1.28 (d, 3H), 1.02 (s, 9H). IR (KBr): 3300, 2240, 1790, 1730,1675, 1610 cm⁻¹ ; MS (m/z)401 (M⁺).

Elemental analysis for C₂₄ H₂₃ N₃ O₃ Calc'd: C, 71.80; H, 5.74; N,10.47. Found: C, 71.49; H, 5.91; N, 10.18.

EXAMPLE3N-(4-Cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-methanesulfonamide

To a solution of the intermediate of Example 1, second paragraph (1.20g, 4.04 mmol) in N,N-dimethylformamide (36 mL) was added, in oneportion, sodium hydride (as a 60% dispersion ill mineral oil; 0.178 g,4.45 mmol). The frothy suspension was stirred at room temperature for 15minutes and then at 0° C. for an additional hour. Methanesulfonicanhydride (0.82 g, 4.71 mmol) was added and the reaction mixture wasstirred at 0° C. for 15 minutes and then allowed to warm to roomtemperature. After stirring overnight, the reaction mixture wasconcentrated. The resulting residue was taken up in methylene chlorideand washed with aqueous sodium bicarbonate, brine and water. The organiclayer was dried (Na₂ SO₄) and concentrated to afford a yellow foam whichwas purified by chromatography (CH₃ OH/CH₂ Cl₂) and trituration (diethylether) to afford 0.71 g (47%) of product as an off-white solid: mp190°-191° C.; ¹ H NMR (CDCl₃): δ7.79 (d, 2H), 7.54 (d, 2H), 6.77 (d,1H), 4.29 (m, 1H), 3.24 (s, 3H), 1.24 (d, 3H), 0.96 (s, 9H). IR (KBr):3350, 2220, 1800, 1725, 1610 cm⁻¹ ; MS (m/z) 375 (M⁺).

Elemental analysis for C₁₈ H₂₁ N₃ O₄ S Calc'd: C, 57.58; H, 5.64; N,11.19. Found: C, 57.60; H, 5.61; N, 11.10.

EXAMPLE 4N-(4-Cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-formamide

To a solution of the intermediate of Example 1, second paragraph (1.20g, 4.04 mmol) in N,N-dimethylformamide (36 mL) was added, in oneportion, sodium hydride (as a 60% dispersion in mineral oil; 0.178 g,4.45 mmol). The frothy suspension was stirred at roomtemperature for 15minutes and then at 0° C. for an additional hour.Trifluoromethanesulfonic anhydride (0.75 mL, 4.46 mmol) was added andthe reaction mixture was stirred at 0° C. for 15 minutes and thenallowed to warm to room temperature. After stirring overnight, thereaction mixture was concentrated. The resulting residue was taken up inmethylene chloride and washed with aqueous sodium bicarbonate and water.Recovered starting material, which precipitated as a yellow solid duringworkup, was filtered away. The organic layer was dried (Na₂ SO₄) andconcentrated to afford a brown residue which was purified bychromatography (CH₃ OH/CH₂ Cl₂), trituration (diethyl ether) andrecrystallization (EtOAc/Hex) to afford 0.12 g (9%) of product as alight yellow solid: mp 187°-190° C.; ¹ H NMR (CDCl₃): δ10.28 (s, 1H),8.33 (s, 1H), 7.67 (d, 2H), 7.58 (d, 2H), 5.07 (m, 1 H), 1.55 (d, 3H),1.04 (s, 9H). IR (KBr): 3400, 2220, 1800, 1740, 1690, 1620 cm⁻¹ ; MS(m/z) 325 (M⁺).

Elemental analysis for C₁₈ H₁₉ N₃ O₃ Calc'd: C, 66.44; H, 5.89; N,12.91. Found: C, 66.29; H, 5.76; N, 12.74.

EXAMPLE 5 Hexanoic Acid(4-cyano-phenyl)-[3,4-dioxo-2-(1.2.2-trimethylpropylamino)-cyclobut-1-enyl]-amide

To a suspension of the intermediate of Example 1, second paragraph (0.70g, 2.35 mmol) in pyridine (9 mL) was added hexanoic anhydride (1.50 mL,6.48 mmol). The mixture was stirred overnight, stripped free of solventand diluted with diethyl ether. A yellow solid (recovered startingmaterial) which remained undissolved was filtered away. The filtrate wasconcentrated, dissolved in methylene chloride and stirred vigorously inthe presence of an equal volume of dilute aqueous sodium bicarbonate.After 30 minutes the organic layer was removed, dried (Na₂ SO₄) andconcentrated. The resulting yellow film was purified by chromatography(CH₃ OH/CH₂ Cl₂) to afford 0.43 g (46%) of product as a pale yellowsolid: mp 51°-65° C.; ¹ H NMR (CDCl₃): δ7.81 (d, 2H), 7.48-7.38 (m, 3H),4.28 (m, 1H), 2.13 (m, 2H), 1.60 (m, 2H), 1.29-1.13 (m, 7H), 0.99 (s,9H), 0.86 (t, 3H). IR (KBr): 3340, 2230, 1800, 1725, 1610 cm^(-1;) MS(m/z) 395 (M⁺).

Elemental analysis for C₂₃ H₂₉ N₃ O₃ Calc'd: C, 69.85; H, 7.39; N,10.62. Found: C, 69.69; H, 7.35; N, 10.50.

EXAMPLE 6N-(4-Cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-isobutyramide

To a solution of iso-butyric anhydride (0.42 mL, 2.53 mmol) in pyridine(9 mL) was added the intermediate of Example 1, second paragraph (0.75g, 2.52 mmol). After stirring overnight additional anhydride (3.8 mL,22.9 mmol) was added and stirring was continued for a second day. Themixture was stripped free of solvent and diluted with diethyl ether. Ayellow solid (recovered starting material) which remained undissolvedwas filtered away. The filtrate was concentrated and the resultingyellow oil was purified by chromatography (CH₃ OH/CH₂ Cl₂) andtrituration (diethyl ether) to afford 0.47 g (51%) of product as a paleyellow solid: mp 175°-176° C.; ¹ H NMR (CDCl₃): δ7.81 (d, 2H), 7.47 (d,2H), 7.42 (d, 1H), 4.28 (m, 1H), 2.52 (m, 1H), 1.27 (d, 3H), 1.10 (m,6H), 1.00 (s, 9H). IR (KBr): 3330, 2230, 1800, 1730, 1680, 1610 cm⁻¹ ;MS (m/z) 367 (M⁺).

Elemental analysis for C₂₁ H₂₅ N₃ O₃ Calc'd: C, 68.64; H, 6.86; N,11.44. Found: C, 68.34; H, 6.75; N, 11.26.

EXAMPLE 7N-(4-Cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)cyclobut-1-enyl]-3-phenyl-acrylamide

To a suspension of the intermediate of Example 1, second paragraph (0.50g, 1.68 mmol) in pyridine (6 mL) was added cinnamic anhydride (0.94 g,3.38 mmol). After stirring overnight, the mixture was concentrated. Theresulting residue was taken up in methylene chloride and washed withaqueous sodium bicarbonate and water. The organic layer was dried (Na₂SO₄) and concentrated to afford a yellow gum which was purified bychromatography (CH₃ OH/CH₂ Cl₂) and trituration (diethyl ether) toafford 0.24 g (47%) of product as an off-white solid: mp 235°-237° C.; ¹H NMR (CDCl₃): δ7.80-7.61 (m, 3H), 7.50-7.32 (m, 8H), 6.21 (d, 1H), 4.32(m, 1H), 1.29 (d, 3H), 1.03 (s, 9H). IR (KBr): 3330, 2220, 1800, 1730,1620, 1600 cm^(-1;) MS (m/z) 427 (M⁺).

Elemental analysis for C₂₆ H₂₅ N₃ O₃.(0.06CH₂ Cl₂).(0.13Et₂ O) Calc'd:C, 72.19; H, 6.02; N, 9.50. Found: C, 72.23; H, 5.96; N, 9.58.

EXAMPLE 8N-(4-Cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-carbamicAcid Ethyl Ester

To a stirred solution of trimethylacetic acid (0.38 g, 3.72 mmol) intetrahydrofuran (5 mL) at 0° C. was added, in order,N,N-diisopropylethylamine (0.65 mL, 3.73 mmol) and (after 10 minutes)ethyl chloroformate (0.36 mL, 3.77 mmol). The resulting suspension oftrimethylacetyl ethyl carbonate was stirred for 30 minutes before use inthe following step.

To a solution of the intermediate of Example 1, second paragraph (1.00g, 3.36 mmol) in N,N-dimethylformamide (30 mL) was added, in oneportion, sodium hydride (as a 60% dispersion in mineral oil; 0.150 g,3.75 mmol). The frothy suspension was stirred at room temperature for 15minutes and at 0° C. for an additional hour. The mixed anhydridesuspension prepared in the preceding paragraph was added all at once.After stirring at room temperature overnight, additional sodium hydride(0.134 g, 3.35 mmol) was added and stirring was continued for a secondnight. The reaction solution was concentrated and the resulting residuewas taken up in methylene chloride and washed with aqueous sodiumbicarbonate and water. Unreacted starting material, which precipitatedas a yellow solid during workup, was filtered away. The organic layerwas dried (Na₂ SO₄) and concentrated to afford a brown gum which waspurified by chromatography (CH₃ OH/CH₂ Cl₂) and trituration (diethylether) to afford 0.20 g (16%)of N-(4-cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-carbamic acidethyl ester as a white solid: mp 158°-159° C.; ¹ H NMR (DMSO-d₆): δ8.18(d, 2H), 7.88 (d, 2H), 7.59 (d, 2H), 4.35-4.07 (m, 3H), 1.23 (t, 3H),1.19 (d, 3H), 0.91 (s, 9H). IR (KBr): 3340, 2230, 1800, 1720, 1620 cm⁻¹; MS (m/z) 369 (M⁺).

Elemental analysis for C₂₀ H₂₃ N₃ O₄ Calc'd: C, 65.03; H, 6.28; N,11.37. Found: C, 64.97; H, 6.19; N, 11.17.

EXAMPLE 9N-(4-Cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-acetamide

The intermediate of Example 1, second paragraph (1.0 g, 3.36 mmol),acetic anhydride (0.95 mL, 10.0 mmol), and pyridine (10 mL) were mixedand allowed to stand at room temperature for 24 hours. The reactionmixture was filtered, and the solid was washed with ethyl acetateyielding 0.84 g (76%) of a yellow solid: mp 284°-286° C. (dec); ¹ H NMR(CDCl₃): δ7.82 (d, 2H), 7.47 (d, 2H), 7.38 (br d, 1H), 4.27 (dq, 1H),2.02 (s, 3H), 1.25 (d, 3H), 0.99 (s, 9H). IR (KBr): 3358, 2978, 2236,1804, 1739, 1685, 1614 cm^(-1;) MS (m/z) 339 (M⁺).

Elemental analysis for C₁₉ H₂₁ N₃ O₃ Calc'd: C, 67.24; H, 6.24; N,12.38. Found: C, 67.15; H, 6.19; N, 12.38.

EXAMPLE 10(R)-(-)-N-(4-Cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-acetamide

4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile (1 g, 4.1 mmol)and a solution of (R)-1,2,2-trimethylpropylamine (8.2 mmol) in ethanol(50 mL) were stirred at room temperature for 24 hours. The resultingyellow slurry was filtered and rinsed with ethyl acetate to yield 0.92 g(75%) of(+)-(R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-benzonitrileas a yellow solid: spectral data was identical to the product of Example1, paragraph 2, except with [α]_(D) ²⁵ =+12° (DMSO, c 0.009).

(R)-(-)-N-(4-Cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-acetamidewas prepared according to the procedure described in Example 9. From theintermediate of the preceding paragraph (0.22 g, 0.74 mmol) and aceticanhydride (0.21 mL, 2.2 mmol) in pyridine (2.2 mL) there was obtained0.1 g (40%) of a yellow solid: spectral data was identical to theproduct of Example 9, except with [α]_(D) ²⁵ =264° (DMSO, c 0.009).

EXAMPLE 11N-(4-Cyano-phenyl)-N-[3,4-dioxo-2-isopropylamino-cyclobut-1-enyl]-acetamide

4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile (1 g, 4.1 mmol)and isopropylamine (5 g, 84.6 mmol) in acetonitrile (125 mL) werestirred at room temperature for 24 hours. The resulting yellow slurrywas filtered to give 0.78 g (31%) of4-[3,4-dioxo-2-isopropylamino)-cyclobut-1-enylamino]-benzonitrile as ayellow solid: mp 290°-292° C. (dec); ¹ H NMR (DMSO-d₆): δ9.89 (br s,1H), 7.77 (d overlapping a br d, 3H), 7.58 (d, 2H), 4.19 (m, 1H), 1.25(d, 6H). IR (KBr): 3200, 3178, 2239, 1794, 1665, 1608, 1576, 1524 cm⁻¹ ;MS (m/z)255 (M⁺).

Elemental analysis for C₁₄ H₁₃ N₃ O₂ Calc'd: C, 65.87; H, 5.13; N,16.46. Found: C, 65.39; H, 4.92; N, 16.41.

N-(4-Cyano-phenyl)-N-[3,4-dioxo-2-isopropylamino)-cyclobut-1-enyl]-acetamidewas prepared according to the procedure described in Example 9. From thereactant of the preceding paragraph (0.15 g, 0.59 mmol) and aceticanhydride (0.28 mL, 2.9 mmol) in pyridine (1.8 mL) there was obtained0.1 g (57%) of pale yellow crystals: mp 187°-188° C.: ¹ H NMR (CDCl₃):δ7.82 (d, 2H), 7.45 (d, 2H), 7.22 (br d, 1H), 4.57 (m, 1H), 2.00 (s,3H), 1.33 (d, 6H). IR (KBr): 3339, 2980, 2239, 1760, 1734, 1695, 1620cm⁻¹ ; MS (m/z) 297 (M⁺).

Elemental analysis for C₁₆ H₁₅ N₃ O₃ Calc'd: C, 64.64; H, 5.08; N,14.13. Found: C, 64.32; H, 4.83; N, 14.13.

EXAMPLE 12N-{2-[Acetyl-(2,2,3,3,3-pentafluoro-propyl)-amino]-3,4-dioxo-cyclobut-1-enyl}-N-(4-cyano-phenyl)-acetamide

4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile (1 g, 4.1 mmol)and 2,2,3,3,3-pentafluoropropylamine (3 mL) in ethanol were refluxed for24 hours. The reaction mixture was filtered and the resulting solid wastriturated with diethyl ether to give 1.0 g (71%) of4-[3,4-dioxo-2-(2,2,3,3,3-pentafluoro-propylamino)-cyclobut-1-enylamino]-benzonitrileas a yellow solid: mp 272°-275° C. (dec); ¹ H NMR (DMSO-d₆): δ10.15 (brs, 1H), 8.19 (br s, 1H), 7.81 (d, 2H), 7.79 (d, 2H), 4.54 (dt, 2H). IR(KBr): 3185, 2239, 1804, 1672, 1608, 1565, 1548 cm⁻¹ ; MS (m/z) 346([M+H]⁺).

Elemental analysis for C₁₄ H₈ F₅ N₃ O₂ Calc'd: C, 48.71; H, 2.34; N,12.17. Found: C, 48.89; H, 2.11; N, 12.21.

The product of the preceding paragraph (0.13 g, 0.38 mmol), aceticanhydride (0.11 mL, 1.1 mmol), and pyridine (1.1 mL) were mixed andallowed to stand at room temperature for 24 hours. The reaction mixturewas diluted with ethyl acetate, filtered, and concentrated under reducedpressure. The resulting residue was taken up in hot ethyl acetate andfiltered hot. The solution was allowed to cool to room temperature andhexanes was added to aid in the crystallization. The solid was filteredand rinsed sparingly with ethyl acetate to give 0.10 g (63%) ofN-{2-[acetyl-(2,2,3,3,3-pentafluoro-propyl)-amino]-3,4-dioxo-cyclobut-1-enyl}-N-(4-cyanophenyl)-acetamideas a pale yellow solid: mp 187°-195° C. (dec); ¹ H NMR (CDCl₃): δ7.83(d, 2H), 7.53 (d, 2H), 4.82 (br m, 2H), 2.37 (s, 3H), 2.07 (s, 3H). IR(KBr): 3435, 2237, 1805, 1772, 1734, 1707, 1603 cm⁻¹ ; MS (m/z) 429(M⁺).

Elemental analysis for C₁₈ H₁₂ F₅ N₃ O₄ Calc'd: C, 50.36; H, 2.82; N,9.79. Found: C, 50.62; H, 2.64; N, 9.86.

EXAMPLE 13N-(4-Cyano-phenyl)-N-[2-(1,2-dimethyl-propylamino)-3,4-dioxo-cyclobut-1-enyl]-acetamide

This compound was prepared according to the procedure described inExample 11, first paragraph.4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)benzonitrile (1 g, 4.1 mmol)and (+)-1,2-dimethylpropylamine (5 g, 57.4 mmol) in acetonitrile (125mL) there was obtained after trituration with methanol 0.28 g (24%) of4-[2-(1,2-dimethyl-propylamino)-3,4-dioxo-cyclobut-1-enylamino)-benzonitrileas a yellow solid: mp 222°-224° C.; ¹ H NMR (DMSO-d₆): δ9.89 (br s, 1H),7.78 (d, 2H), 7.73 (d, 1H), 7.59 (d, 2H), 3.98 (m, 1H), 1.76 (m, 1H),1.19 (d, 3H), 0.90 (d, 3H), 0.89 (d, 3H). IR (KBr): 2980, 2240, 1799,1660, 1600, 1565, 1525 cm⁻¹ ; MS (m/z) 283 (M⁺).

Elemental analysis for C₁₆ H₁₇ N₃ O₂ Calc'd: C, 67.83; H, 6.05; N,14.83. Found: C, 67.32: H, 5.94; N, 14.91.

N-(4-Cyano-phenyl)-N-[2-(1,2-dimethyl-propylamino)-3,4-dioxo-cyclobut-1-enyl]-acetamidewas prepared according to the procedure described in Example 9. From theproduct of the preceding paragraph (0.27 g, 0.95 mmol) and aceticanhydride (0.27 mL, 2.9 mmol) in pyridine (2.9 mL) there was obtained0.17 g (55%) of white crystals: mp 258°-262° C. (dec); ¹ H NMR (CDCl₃):δ7.82 (d, 2H), 7.46 (d, 2H), 7.29 (br d, 1H), 4.30 (m, 1H), 2.02 (s,3H), 1.81 (m, 1H), 1.27 (d, 3H), 1.00 (d, 3H), 0.99 (d, 3H). IR (KBr):3337, 2967, 2228, 1804, 1739, 1685, 1620 cm⁻¹ ; MS (m/z) 325 (M⁺).

Elemental analysis for C₁₈ H₁₉ N₃ O₃ Calc'd: C, 66.45; H, 5.87; N,12.91. Found: C, 66.48; H, 5.82; N, 12.79.

EXAMPLE 14N-(3-Cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-acetamide

3-Aminobenzonitrile (2.06 g, 17.4 mmol) and3,4-diethoxy-3-cyclobutene-1,2-dione (2.97 g, 17.5 mmol) in absoluteethanol (50 mL) was refluxed overnight. The reaction mixture wasfiltered hot, then allowed to cool to room temperature. The resultingprecipitate was filtered to give 3.4 g of a yellow solid which was usedwithout further purification. This yellow solid (1 g, 4.1 mmol) and2-amino-3,3-dimethylbutane (2 g, 19.8 mmol) in acetonitrile (125 mL)were stirred at room temperature for 24 hours. The reaction mixture wasfiltered to give 0.66 g (54%) of3-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-benzonitrileasa pale yellow solid: mp 296°-298° C. (dec); ¹ H NMR (DMSO-d₆): δ9.79 (brs, 1H), 7.94 (br s, 1H), 7.67 (d, 1H), 7.64 (dm, 1H), 7.53 (t, 1H), 7.45(dm, 1H), 3.98 (m, 1H), 1.17 (d, 3H), 0.91 (s, 9H). IR (KBr): 3193,3148, 2974, 2228, 1793, 1673, 1582, 1544 cm⁻¹ ; MS (m/z) 297 (M⁺).

Elemental analysis for C₁₇ H₁₉ N₃ O₂ Calc'd: C, 68.67; H, 6.44; N,14.13. Found: C, 68.73; H, 6.36; N, 14.04.

N-(3-Cyano-phenyl)-N-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-acetamidewas prepared according to the procedure described in Example 9. From theproduct of the preceding paragraph (0.18 g, 0.61 mmol) and aceticanhydride (0.28 mL, 3.0 mmol) in pyridine (1.8 mL) there was obtained0.14 g (68%) of white crystals: mp 253°-254° C.; ¹ H NMR (CDCl₃): δ7.81(dt, 1H), 7.69-7.58 (m, 3H), 7.41 (br d, 1H), 4.27 (m, 1H), 2.01 (s,3H), 1.25 (d, 3H), 0.99 (s, 9H). IR (KBr): 3337, 2965, 2237, 1804, 1739,1684, 1619 cm⁻¹ ; MS (m/z) 339 (M⁺).

Elemental analysis for C₁₉ H₂₁ N₃ O₃ Calc'd: C, 67.24; H, 6.24; N,12.38. Found: C, 67.21; H, 6.20; N, 12.38.

EXAMPLE 15(R)-N-(4-Cyano-phenyl)-N-[2-(1-cyclohexyl-ethylamino)-3,4-dioxo-cyclobut-1-enyl]acetamide

(R)-4-[2-(1-Cyclohexyl-ethylamino)-3,4-dioxo-cyclobut-1-enylamino]-benzonitrilewas prepared according to the procedure described in Example 10, firstparagraph. From 4-(3,4-dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile(0.36 g, 1.5 mmol) and (R)-(-)-1-cyclohexylethylamine (0.29 mL, 1.95mmol) in absolute ethanol (5 mL) there was obtained after triturationwith hot methanol 0.31 g (64%) of a yellow solid: mp 275°-280° C. (dec);¹ H NMR (DMSO-d₆): δ9.87 (br s, 1H), 7.78 (d, 2H), 7.72 (d, 1H), 7.59(d, 2H), 3.96 (m, 1H), 1.78-1.66 (m, 4H), 1.62 (m, 1H), 1.34 (m, 1H),1.24-0.90 (m including a doublet at δ1.20, 8H). IR (KBr): 3200, 2920,2850, 2220, 1790, 1660, 1600, 1560, 1528 cm⁻¹ ; MS (m/z) 323 (M⁺).

Elemental analysis for C₁₉ H₂₁ N₃ O₂ Calc'd: C, 70.57; H, 6.55; N,12.99. Found: C, 70.19; H, 6.60; N, 13.00.

This compound was prepared according to the procedure described inExample 12, second paragraph. From the product of the precedingparagraph (0.33 g, 1.02 mmol) and acetic anhydride (0.29 mL, 3.06 mmol)in pyridine (3.1 mL) there was obtained 0.62 g (40%) of(R)-N-(4-cyano-phenyl)-N-[2-(1-cyclohexylethylamino)-3,4-dioxo-cyclobut-1-enyl]-acetamideas a yellow solid: mp 194°-198° C.; [α]_(D) ²⁵ =-150.96° (DMSO, c0.0084); ¹ H NMR (CDCl₃): δ7.82 (d, 2H), 7.46 (d, 2H), 7.25 (br m, 1H),4.28 (m, 1H), 2.02 (s, 3H), 1.87-0.94 (m including a doublet at δ1.27,14H). IR (KBr): 3337, 2930, 2865, 2237, 1803, 1729, 1690, 1620 cm^(-1;)MS (m/z) 365 (M⁺).

Elemental analysis for C₂₁ H₂₃ N₃ O₃ Calc'd: C, 69.02; H, 6.34; N,11.50. Found: C, 68.7.9.2; H, 6.10; N, 11.55.

EXAMPLE 16N-(2-Butylamino-3,4-dioxo-cyclobut-1-enyl)-N-(4-cyano-phenyl)-acetamide

4-[2-Butylamino-3,4-dioxo-cyclobut- 1-enylamino)-benzonitrile wasprepared according to the procedure described in Example 11, firstparagraph. From 4-(3,4-dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile(1 g, 4.1 mmol) and butylamine (3 g, 41.0 mmol) in acetonitrile (125 mL)there was obtained 0.64 g (58%) of a yellow solid: nip 256°-258° C.(dec); ¹ H NMR (DMSO-d₆): δ10.00 (br s, 1H), 7.81 (br s, 1H), 7.77 (d,2H), 7.57 (d, 2H), 3.60 (br q, 2H), 1.55 (quintet, 2H), 1.34 sextet,2H), 0.90 (t, 3H). IR (KBr): 3240, 2980, 2240, 1800, 1670, 1625, cm⁻¹ ;MS (m/z) 269 (M⁺).

Elemental analysis for C₁₅ H₁₅ N₃ O₂ Calc'd: C, 66.90; H, 5.61; N,15.60. Found: C, 66.23; H, 5.80; N, 15.54.

N-(2-Butylamino-3,4-dioxo-cyclobut-1-enyl)-N-(4-cyano-phenyl)-acetamidewas prepared according to the procedure described in Example 12,paragraph two. From the product of the preceding paragraph (0.16 g, 0.59mmol) and acetic anhydride (0.28 mL, 2.96 mmol) in pyridine (1.8 mL)there was obtained 0.05 g (27%) of white solid: mp 194°-196° C.; ¹ H NMR(CDCl₃): δ7.82 (d, 2H), 7.45 (d, 2H), 7.34 (br m, 1H), 3.78 (q, 2H),2.01 (s, 3H), 1.65 (quintet, 2H), 1.44 (sextet, 2H), 0.98 (t, 3H). IR(KBr): 3315, 2957, 2228, 1796, 1727, 1696, 1598 cm⁻¹ ; MS (m/z) 311(M⁺).

Elemental analysis for C₁₇ H₁₇ N₃ O₃ Calc'd: C, 65.58; H, 5.50; N,13.50. Found: C, 65.45; H, 5.63; N, 13.45.

EXAMPLE 17N-(endo)-[2-(Bicyclo[2.2.1]hept-2-ylamino)-3,4-dioxo-cyclobut-1-enyl]-N-(4-cyano-phenyl)-acetamide

(endo)-4-[2-(Bicyclo[2.2.1]hept-2-ylamino)-3,4-dioxo-cyclobut-1-enylamino]-benzonitrilewas prepared according to the procedure described in Example 11, firstparagraph. From 4-(3,4-dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile(0.37 g, 1.5 mmol) and (+)-endo-2-aminonorbornane (0.17 g, 1.5 mmol) inacetonitrile (30 mL) there was obtained after trituration with diethylether 0.32 g (69%) of a yellow solid: mp 251°-252° C. (dec); ¹ H NMR(DMSO-d₆): δ9.88 (br s, 1H), 7.85 (d, 1H), 7.78 (d, 2H), 7.60 (d, 2H),4.35 (m, 1H), 2.36 (m, 1H), 2.23 (m, 1H), 2.2 (m, 1H), 1.69-1.23 (m,6H), 0.91 (m, 1H). IR (KBr): 3200, 2942, 2220, 1798, 1668, 1600, 1565,1535 cm⁻¹ : MS (m/z) 307 (M⁺ ).

Elemental analysis for C₁₈ H₁₇ N₃ O₂ Calc'd: C, 70.34: H, 5.57; N.13.67. Found: C, 70.03; H, 5.38; N, 13.97.

N-(endo)-[2-(Bicyclo[2.2.1]hept-2-ylamino)-3,4-dioxo-cyclobut-1-enyl]-N-(4-cyano-phenyl)-acetamidewas prepared according to the procedure described in Example 9. From theproduct of the preceding paragraph (0.021 g, 0.068 mmol) and aceticanhydride (0.033 mL, 0.35 mmol) in pyridine (0.21 mL) there was obtained0.014 g (59%) of pale yellow solid: mp 282°-285° C. (dec); ¹ H NMR(CDCl₃): δ7.82 (d, 2H), 7.45 (d, 2H), 7.51 (br d, 1H), 4.63 (m, 1H),2.48 (m, 1H), 2.31 (m, 1H), 2.20 (m, 1H), 2.02 (s, 3H), 1.75-1.30 (m,6H), 0.96 (m, 1H). IR (KBr): 3343, 2957, 2239, 1803, 1730, 1690, 1620cm⁻¹ ; MS (m/z) 349 (M⁺).

Elemental analysis for C₂₀ H₁₉ N₃ O₃ Calc'd: C, 68.75; H, 5.48; N,12.03. Found: C, 68.39; H, 5.39; N, 12.02.

EXAMPLE 18N-(2-tert-Butylamino-3,4-dioxo-cyclobut-1-enyl)-N-(isoquinolin-5-yl)-acetamide

5-Aminoisoquinoline (4.24 g, 29.4 mmol) and3,4-diethoxy-3-cyclobutene-1,2-dione (5 g, 29.4 mmol) in absoluteethanol (100 mL) were refluxed overnight. The reaction mixture wasfiltered to give 2.3 g of a solid which was used without furtherpurification. This solid (0.3 g, 1.12 mmol) in tert-butylamine (50 mL)was refluxed for 3 hours. The reaction mixture was concentrated andtriturated with diethyl ether to give 0.12 g (39%) of3-tert-Butylamino-4-(isoquinolin-5-ylamino)-cyclobut-3-ene-1,2-dione asa white solid 0.125 hydrate: mp 268°-270° C. (dec); ¹ H NMR (DMSO-d₆):δ9.75 (s, 1H), 9.35 (s, 1H), 8.62 (d, 1H), 8.19 (s, 1H), 8.01 (d, 1H),7.88 (d, 1H), 7.80 (d, 1H), 7.68 (t, 1H), 1.47 (s, 9H). IR (KBr): 3200,1785, 1670, 1600 cm⁻¹ : MS (m/z) 295 (M⁺).

Elemental analysis for C₁₇ H₁₇ N₃ O₂.0.125H₂ O Calc'd: C, 69.14; H,5.80: N, 14.23. Found: C, 68.08; H, 5.78: N, 13.7.

N-(2-tert-Butylamino-3,4-dioxo-cyclobut-1-enyl)-N-(isoquinolin-5-yl)-acetamidewas prepared according to the procedure described in Example 12, secondparagraph. From the product of the preceding paragraph (0.30 g, 1.0mmol) and acetic anhydride (0.29 mL, 3.0 mmol) in pyridine (3 mL) therewas obtained 0.18 g (53%) of off-white crystals: mp 210°-213° C.; ¹ HNMR (CDCl₃): δ9.41 (s, 1H), 8.66 (d, 1H), 8.19 (m, 1H), 8.09 (br s, 1H),7.81-7.72 (m, 2H), 7.59 (d, 1H), 1.89 (s, 3H), 1.56 (s, 9H). IR (KBr):3304, 2965, 1793, 1679, 1588 cm⁻¹ ; MS (m/z) 337 (M⁺).

Elemental analysis for C₁₉ H₁₉ N₃ O₃ Calc'd: C, 67.64; H, 5.68: N,12.46. Found: C, 67.38; H, 5.65: N, 12.41.

EXAMPLE 19N-(2-tert-Butylamino-3,4-dioxo-cyclobut-1-enyl)-N-(pyridin-3-yl)-acetamide

3-Aminopyridine (2.77 g, 29.4 mmol) and3,4-diethoxy-3-cyclobutene-1,2-dione (5 g, 29.4 mmol) in absoluteethanol (150 mL) were refluxed for 18 hours. The reaction mixture wasconcentrated and chromatographed in hexanes/ethyl acetate (1/4) to give3.15 g of a white solid. This solid (2.6 g, 11.9 mmol) intert-butylamine (50 mL) was refluxed for 3 hours. The reaction mixturewas concentrated and triturated with diethyl ether to give 1.05 g (36%)of 3-tert-butylamino-4-(pyridin-3-ylamino)-cyclobut-3-ene-1,2-dione as awhite solid: mp 250°-252° C. (dec); ¹ H NMR (DMSO-d₆): δ8.57 (s, 1H),8.23 (d, 1H), 7.96 (d, 1H), 7.37 (m, 1H), 1.43 (s, 9H). IR (KBr): 1790,1685, 1600 cm⁻¹ ; MS (m/z) 245 (M⁺).

Elemental analysis for C₁₃ H₁₅ N₃ O₂ Calc'd: C, 63.66; H, 6.16; N,17.13. Found: C, 63.28; H, 6.22: N, 17.07.

N-(2-tert-Butylamino-3,4-dioxo-cyclobut-1-enyl)-N-(pyridin-3-yl)-acetamidewas prepared according to the procedure described in Example 12, secondparagraph. From the product of the preceding paragraph (0.20 g, 0.82mmol) and acetic anhydride (0.23 mL, 2.5 mmol) in pyridine (2.5 mL)there was obtained 0.15 g (68%) of white crystals: mp 194°-195° C.; ¹ HNMR (CDCl₃): δ8.74 (d, 1H), 8.62 (s, 1H), 7.83 (br s, 1H), 7.70 (m, 1H),7.47 (dd, 1H), 2.00 (s, 3H), 1.52 (s, 9H). IR (KBr): 3435, 3298, 1799,1741, 1685, 1598 cm⁻¹ : MS (m/z) 288 ([M+H]⁺).

Elemental analysis for C₁₅ H₁₇ N₃ O₃ Calc'd: C, 62.71; H, 5.96; N,14.62. Found: C, 62.78; H, 5.91: N, 14.67.

EXAMPLE 20N-[3.4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-N-(2-methoxy-5-trifluoromethyl-phenyl)-acetamide

2-Methoxy-5-trifluoromethylaniline (5.62 g, 29.4 mmol) and3,4-diethoxy-3-cyclobutene-1,2-dione (5 g, 29.4 mmol) in absoluteethanol (100 mL) were refluxed for 66 hours. The reaction mixture wasfiltered and the precipitate was chromatographed in methanol/methylenechloride to give 1.88 g of a yellow solid. This solid (1.0 g, 3.2 mmol)and 2-amino-3,3-dimethylbutane (0.43 mL, 3.2 mmol) in absolute ethanol(20 mL) were stirred at room temperature for 18 hours. The reactionmixture was concentrated and chromatographed with methylenechloride/methanol (96:4) to give 0.91 g (78%) of3-ethoxy-4-(2-methoxy-5-trifluoromethyl-phenylamino)-cyclobut-3-ene-1,2-dioneas a white solid: mp 143°-155° C.; ¹ H NMR (DMSO-d₆): δ9.36 (s, 1H),8.24 (d, 1H), 8.19 (d, 1H), 7.35 (dd, 1H), 3.99 (s, 3H), 1.18 (d, 3H),0.91 (s, 9H). IR (KBr): 3293, 2976, 1802, 1690, 1591, 1543 cm⁻¹ ; MS(m/z) 370 (M⁺).

Elemental analysis for C₁₈ H₂₁ F₃ N₂ O₃ Calc'd: C, 58.37; H, 5.72; N,7.56. Found: C, 57.98; H, 5.65; N, 7.27.

N-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-N-(2-methoxy-5-trifluoromethyl-phenyl)-acetamidewas prepared according to the procedure described in Example 12, secondparagraph. From the product of the preceding paragraph (0.20 g, 0.54mmol) and acetic anhydride (0.15 mL, 1.6 mmol) in pyridine (1.6 mL)there was obtained 0.16 g (73%) of white crystals: mp 76°-79° C.; ¹ HNMR (CDCl₃): δ7.73 (dd, 1H), 7.53 (d, 1H), 7.38 (br d, 1H), 7.12 (d,1H), 4.25 (m, 1H), 3.92 (s, 3H), 1.96 (s, 3H), 1.24 (d, 3H), 1.00 and0.99 (two singlets, 9H). IR (KBr): 3326, 2974, 1799, 1715, 1609 cm⁻¹ ;MS (m/z) 412 (M⁺).

Elemental analysis for C₂₀ H₂₃ F₃ N₂ O₄ Calc'd: C, 58.25; H, 5.62: N,6.79 Found: C, 58.44; H, 5.85; N, 6.47

EXAMPLE 21(endo)-N-[2-(Bicyclo[2.2.1]hept-2-ylamino)-3,4-dioxo-cyclobut-1-enyl]-N-(pyridin-4-yl)-acetamide

4-Aminopyridine (2.77 g, 29.4 mmol) and3,4-diethoxy-3-cyclobutene-1,2-dione (5 g, 29.4 mmol) in absoluteethanol (100 mL) were refluxed for 4 hours. The reaction mixture wasconcentrated and chromatographed in ethyl acetate to give 0.63 g of awhite solid. This solid (0.33 g, 1.5 mmol) and(+)-(endo)-2-aminonorbornane (0.17 g, 1.5 mmol) in acetonitrile (30 mL)was stirred at room temperature for 24 hours. The reaction mixture wasfiltered and triturated with diethyl ether to give 0.35 g (36%) of(+)-(endo)-3-(bicyclo[2.2.1]hept-2-ylamino)-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dioneas a pale yellow solid 1.56 hydrate: mp 270°-277° C. (dec); ¹ H NMR(DMSO-d₆): δ9.81 (br s, 1H), 8.41 (d, 2H), 7.88 (d, 1H), 7.44 (d, 2H),4.34 (m, 1 H), 2.35 (m, 1H), 2.23 (m, 1H), 2.10 (m, 1H), 1.69-1.20 (m,6H), 0.90 (m, 1H). IR (KBr): 3365, 295 7, 1799, 1691, 1630, 1599, 1533cm⁻¹ ; MS (m/z)283 (M⁺).

Elemental analysis for C₁₆ H₁₇ N₃ O₂.1.56H₂ O Calc'd: C, 61.71; H, 6.51;N, 13.49. Found: C, 61.76; H, 6.37 N, 13.27.

(endo)-N-[2-{Bicyclo[2.2.1]hept-2-ylamino)-3,4-dioxo-cyclobut-1-enyl]-N-(pyridin-4-yl)-acetamidewas prepared according to the procedure described in Example 12, secondparagraph. From the product of the preceding paragraph (0.17 g, 0.60mmol) and acetic anhydride (0.28 mL, 3.0 mmol) in pyridine (1.8 mL)there was obtained 0.08 g (41%) of pale yellow solid: mp 192°-194° C.; ¹H NMR (CDCl₃): δ8.80 (dd, 2H), 7.49 (br d, 1H), 7.30 (dd, 2H), 4.63 (m,1H), 2.48 (m, 1H), 2.3 (m, 1H), 2.19 (m, 1H), 2.06 (s, 3H), 1.75-1.30(m, 6H), 0.97 (m, 1H). IR (KBr): 3348, 2954, 1799, 1735, 1696, 1621cm^(-1;) MS (m/z) 325 ([M+H]⁺).

Elemental analysis for C₁₈ H₁₉ N₃ O₃ Calc'd: C, 66.45; H, 5.89; N,12.91. Found: C, 66.02; H, 5.87; N, 12.66.

EXAMPLE 22N-(2-sec-Butylamino-3,4-dioxo-cyclobut-1-enyl)-N-(4-cyano-phenyl)acetamide

4-[2-sec-Butylamino-3,4-dioxo-cyclobut-1-enylamino)-benzonitrile wasprepared according to the procedure described in Example 11, firstparagraph. From 4-(3,4-dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile(1 g, 4.1 mmol) and (+)-sec-butylamine (excess) in acetonitrile (125 mL)there was obtained 1.36 g of a yellow solid: mp 245°-247° C.; ¹ H NMR(DMSO-d₆): δ9.89 (br s, 1H), 7.78 (d, 2H), 7.73 (d, 1H), 7.58 (d, 2H),4.01 (m, 1H), 1.65-1.46 (m 2H), 1.23 (d, 3H), 0.89 (t, 3H). IR (KBr):3217, 3185, 3000, 2228, 1798, 1664, 1609, 1527 cm⁻¹ ; MS (m/z) 269 (M⁺).

Elemental analysis for C₁₅ H₁₅ N₃ O₂ Calc'd: C, 66.90; H, 5.61; N,15.60. Found: C, 66.78; H, 5.43; N, 15.61.

N-(2-sec-Butylamino-3,4-dioxo-cyclobut-1-enyl)-N-(4-cyano-phenyl)-acetamidewas prepared according to the procedure described in Example 12, secondparagraph. From the product of the preceding paragraph (0.16 g, 0.52mmol) and acetic anhydride (0.28 mL, 2.96 mmol) in pyridine (1.8 mL)there was obtained 0.14 g (78%) of yellow crystals: mp 220°-225° C.(dec.); ¹ H NMR (CDCl₃): δ7.80 (d, 2H), 7.44 (d, 2H), 7.14 (br d, 1H),4.36 (m, 1H), 2.00 (s, 3H), 1.71-1.53 (m, 2H), 1.30 (d, 3H), 0.98 (s,3H). IR (KBr): 3348, 2978 2239, 1803, 1739, 1690, 1622 cm⁻¹ ; MS (m/z)311 (M⁺).

Elemental analysis for C₁₇ H₁₇ N₃ O₃ Calc'd: C, 65.58; H, 5.50; N,13.50. Found: C, 65.18; H, 5.31; N, 13.33.

The smooth muscle relaxing activity of the compounds of this inventionwas established in accordance with standard pharmaceutically acceptedtest procedures with representative compounds as follows:

Sprague-Dawley rats (150-200 g) are rendered unconscious by CO₂asphyxiation and then euthanized by cervical dislocation. The bladder isremoved into warm (37 deg. C.) physiological salt solution (PSS) of thefollowing composition (mM): NaCl, 118.4; KCl, 4.7; CaCl₂, 2.5; MgSO₄,4.7; H₂ O, 1.2; NaHCO₃, 24.9; KH₂ PO₄, 1.2; glucose, 11.1; EDTA, 0.023;gassed with 95% O₂ ; 2/5% CO₂ ; pH 7.4. The bladder is opened and thencut into strips 1-2 mm in width and 7-10 mm in length. The strips aresubsequently suspended in a 10 mL tissue bath under an initial restingtension of 1.5 g. The strips are held in place by two surgical clips oneof which is attached to a fixed hook while the other is attached to anisometric force transducer. The preparations, which usually exhibitsmall spontaneous contractions, are allowed to recover for a period of 1hour prior to a challenge with 0.1 uM carbachol. The carbachol is thenwashed out and the tissue allowed to relax to its resting level ofactivity. Following a further 30 min period of recovery an additional 15mM KCl are introduced into the tissue bath. This increase in KClconcentration results in a large increase in the amplitude ofspontaneous contractions (and initiation of contractions in previouslyquiescent strips) superimposed upon a small increase in basal tone.Following stabilization of this enhanced level of contractile activity,incremental increases in the concentration of test compound or vehicleare introduced into the tissue bath. Contractile activity is measuredfor each compound or vehicle concentration during the last minute of a30 minute challenge.

The isometric force developed by the bladder strips is measured using aconcentration required to elicit 50% inhibition of pre-drug contractileactivity (IC₅₀ concentration) is calculated from thisconcentration-response curve. The maximum percentage inhibition ofcontractile activity evoked by a test compound is also recorded forconcentrations of test compound less than or equal to 30 μM.

The results of this study are shown in Table I.

                  TABLE I                                                         ______________________________________                                        Inhibition of Contractions in Isolated Rat Bladder Strips                     Compound        n     IC.sub.50 μM                                         ______________________________________                                        Example 1       2     0.50 ± 0.0                                           Example 2       2     0.29 ± 0.04                                          Example 5       2     0.35 ± 0.1                                           Example 6       4     0.57 ± 0.2                                           Example 7       2     0.37 ± 0.08                                          Example 9       4     0.23 ± 0.05                                          Example 10      2     0.31 ± 0.05                                          Example 11      2     9.7 ± 4.1                                            Example 13      2     0.2 ± 0.1                                            Example 14      2      3.2 ± 0.92                                          Example 16      2     1.24 ± 0.54                                          Example 17      2     1.84 ± 0.36                                          ______________________________________                                    

Hence, the compounds of this invention have a pronounced effect onsmooth muscle contractility and are useful in the treatment of urinaryincontinence, irritable bladder and bowel disease, asthma, hypertension,stroke, and similar diseases as mentioned above, which are amenable totreatment with potassium channel activating compounds by administration,orally, parenterally, or by aspiration to a patient in need thereof.

What is claimed is:
 1. A compound of the formula: ##STR13## wherein: R₁and R₂ are, independent from each other, hydrogen, C₁₋₁₀ straight chainalkyl, C₃₋₁₀ branched alkyl, or C₃₋₁₀ cyclic or bicyclic alkyl;R₃ is anacyl substituent selected from the group consisting of formyl, alkanoylof 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonylof 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoylof 8 to 12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms; Ais selected from the group consisting of: ##STR14## wherein: R₄ ishydrogen, C₁₋₆ alkyl, C₁₋₆ perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆perfluoroalkoxy, amino, C₁₋₆ alkylamino, C₂₋₁₂ dialkylamino, C₁₋₆alkylsulfonamido, alkylcarboxamido containing 2 to 7 carbon atoms,nitro, cyano, carboxyl; or a pharmaceutically acceptable salt thereof.2. A compound of claim 1 in which A is: ##STR15## or a pharmaceuticallyacceptable salt thereof.
 3. A method for reducing the adverse effects ofsmooth muscle contractions which comprises administering, orally orparenterally, to a patient in need thereof, a compound of the formula:##STR16## wherein: R₁ and R₂ are, independent from each other, hydrogen,C₁₋₁₀ straight chain alkyl, C₃₋₁₀ branched alkyl or C₃₋₁₀ cyclic orbicyclic alkyl;R₃ is an acyl substituent selected from the groupconsisting of formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms orarylalkylsulfonyl of 7 to 12 carbon atoms; A is selected from the groupconsisting of: ##STR17## wherein: R₄ is hydrogen, C₁₋₆ alkyl, C₁₋₆perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆ perfluoroalkoxy, amino, C₁₋₆alkylamino, C₂₋₁₂ dialkylamino, C₁₋₆ alkylsulfonamido, alkylcarboxamidocontaining 2 to 7 carbon atoms, nitro, cyano, carboxyl; or apharmaceutically acceptable salt thereof.
 4. The method of claim 3 inwhich the smooth muscle adversely contracting causes urinaryincontinence.
 5. The method of claim 3 in which the smooth muscleadversely contracting causes irritable bowel syndrome.
 6. Apharmaceutical composition comprising a compound as claimed in claim 1in combination or association with a pharmaceutically acceptablecarrier.